A partial clone of the prostaglandin synthase I gene from mouse strain 129 genomic DNA was obtained. A targeting construct was made using 7.5kb of the genomic clone with an inserted bacterial neo gene and trailing herpes simplex virus TK gene. The construct was electroporated into embryonic stem cells and G418/gangcyclovir resistant clones were isolated. Homologously targeted ES cells were identified by Southern and PCR analysis. The targeted ES cells with a single allele of the PHS-1 disrupted have been injected into bastocysts and the blastocysts implanted. The births of chimeric and, subsequently, germline transmitting animals are awaited. These animals will be utilized to determine the role of PHS-1 in carcinogenesis.